WO2005011669A1 - Composition medicamenteuse pour administration percutanee - Google Patents

Composition medicamenteuse pour administration percutanee Download PDF

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Publication number
WO2005011669A1
WO2005011669A1 PCT/JP2004/011385 JP2004011385W WO2005011669A1 WO 2005011669 A1 WO2005011669 A1 WO 2005011669A1 JP 2004011385 W JP2004011385 W JP 2004011385W WO 2005011669 A1 WO2005011669 A1 WO 2005011669A1
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WO
WIPO (PCT)
Prior art keywords
transdermal administration
pharmaceutical composition
carrier
leflunomide
base
Prior art date
Application number
PCT/JP2004/011385
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English (en)
Japanese (ja)
Inventor
Koichi Saito
Toshiyuki Hosokawa
Original Assignee
Dainippon Sumitomo Pharma Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dainippon Sumitomo Pharma Co., Ltd. filed Critical Dainippon Sumitomo Pharma Co., Ltd.
Priority to JP2005512605A priority Critical patent/JPWO2005011669A1/ja
Priority to US10/921,960 priority patent/US20050158371A1/en
Publication of WO2005011669A1 publication Critical patent/WO2005011669A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics

Definitions

  • composition for transdermal administration is provided.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising N- (4-trifluoromethylphenyl) -15-methylisoxazolyl-41-carboxamide or an active metabolite thereof or a pharmacologically acceptable salt thereof as an active ingredient.
  • the present invention relates to a pharmaceutical composition for skin administration. More specifically, the present invention relates to N- (4-trifluoromethylphenyl) -15-methylisoxazolyl_4-carboxamide, or N- (4-trifluoromethyl) which is an active metabolite thereof.
  • N- (4-Trifluoromethylphenyl) -5-methylisoxazolyl-4-carboxamide has an anti-inflammatory and analgesic effect, known as leflunomide, and is represented by the following structural formula Compound.
  • leflunomide an anti-inflammatory and analgesic effect
  • the production method and the like are described in JP-A-55-83767, U.S. Pat. No. 4,087,535, and U.S. Pat. No. 4,284,786.
  • N- (4-Trifluoromethylphenyl) -12-cyano-3-hydroxyhydroxy tonamide is a compound having an anti-inflammatory action and an analgesic action and represented by the following structural formula. It is known as the active metabolite of N- (4-trifluoromethylphenyl) -15-methylisoxazolyl 4-carboxamide, the details of which are described in US Pat. No. 4,061,767. It is described in. For these compounds, therapeutic uses for various diseases and various dosage forms have been proposed.
  • Japanese Patent No. 328552226 discloses that N— (4-trifluoromethylphenysole) _5-methylisosoxazolyl 41-carboxamide or N— (4—trifur Oromethylphenyl) Medication for the treatment of organ transplant recipients for hyperacute or chronic rejection, consisting of 1-cyano 3-hydroxy-crotonamide (or a pharmacologically acceptable salt thereof) Is described. Also, Japanese Patent No. 3131693 contains 5-methyl-isoxazole-4-carboxylic acid anilides and 2-hydroxyethylidene-cyanoacetic acid anilides. An ophthalmic composition for the treatment of dextrose ophthalmitis, retinitis, allergy and xerosis is described.
  • Japanese Patent No. 2,930,281 discloses that N— (4-trifluoromethylphenyl) -15-methylisoxazolyl-14-carboxamide and N— (4-to (Rifluoromethylphenyl)-A skin containing psoriasis, atopic dermatitis, allergic dermatitis, drug-induced dermatitis, etc., containing a specific compound containing 2-cyano-3-hydroxy-crotonamide as an active ingredient Drugs for preventing or treating the disease are described.
  • transdermal administration the drug can be directly administered to the affected area, so that the drug concentration at the affected area can be locally increased.
  • Transdermal preparations can avoid the first-pass effect of the oral preparations in the liver, and can be expected to reduce side effects.
  • it has the advantage that the number of administrations can be reduced and the efficacy of the drug can be maintained.
  • transdermal administration has a great advantage in that administration is easy even for patients who have difficulty in oral administration, and transdermal administration of various drugs is being studied.
  • transcutaneous drugs for the treatment of non-dermatological diseases such as rheumatoid arthritis and arthritis in hydroxyc mouth tonamide (or its pharmacologically acceptable salt).
  • non-dermatological diseases such as rheumatoid arthritis and arthritis in hydroxyc mouth tonamide (or its pharmacologically acceptable salt).
  • no anti-rheumatic and anti-inflammatory effects have been known when these drugs are transdermally administered using a specific carrier.
  • the problem to be solved by the present invention is to provide N- (4-trifluoromethylphenyl) -5-methylisoxazolyl-4-carboxamide, or an active metabolite thereof or a pharmaceutically acceptable salt thereof.
  • An object of the present invention is to provide a novel pharmaceutical composition for transdermal administration having excellent therapeutic effect and stability, comprising a salt as an active ingredient.
  • N- (4_trifluoromethylphenyl) -15-methylisoxazole-14-carboxyamide is an active ingredient.
  • Carrier for transdermal administration containing at least 4 Ow / w% of a dissolution base, or
  • transdermal carrier containing at least 70% by weight of a suspension base that is hydrophobic and has no polar group in the molecule
  • a pharmaceutical composition for transdermal administration comprising: [2] The pharmaceutical composition for transdermal administration according to the above [1], wherein the active metabolite is N- (4-trifluoromethylphenyl) -2-cyano 3-hydroxy-crotonamide.
  • dialkyl dibasic ester is one or more mixtures selected from getyl sebacate, diisopropyl sebacate and diisopropyl adipate.
  • the carrier for transdermal administration is a carrier for transdermal administration containing at least 70 w / w% or more of a suspension base that is hydrophobic and has no polar group in the molecule,
  • composition for transdermal administration according to any of the above-mentioned [15] to [17], wherein the carrier for transdermal administration comprises only a suspension base which is hydrophobic and has no polar group in the molecule.
  • the carrier for transdermal administration comprises only a suspension base which is hydrophobic and has no polar group in the molecule.
  • An N- (4-trifluoromethyl) for producing a therapeutic agent for rheumatoid arthritis or arthritis for transdermal administration comprising the composition for transdermal administration according to [1].
  • Carrier for transdermal administration containing at least 40% w / w of a dissolution base, or
  • a carrier for transdermal administration containing at least 70% by weight or more of a suspending base that is hydrophobic and has no polar group in the molecule;
  • a method for treating rheumatoid arthritis or arthritis which comprises transdermally administering a pharmaceutical composition for percutaneous administration, comprising:
  • the transdermal carrier is a transdermal carrier containing at least 40 ww% or more of a dissolution base, and is transdermal in a state where the active ingredient is dissolved in the transdermal carrier.
  • the pharmaceutical composition for transdermal administration containing the leflunomide of the present invention exhibits an anti-inflammatory effect and an anti-rheumatic effect when administered directly to the skin near the affected part as an external preparation. Further, the medicament and composition for transdermal administration of the soluble type of the present invention and the medicinal composition for transdermal administration of the suspension type can stably retain leflunomides and have excellent preparation stability.
  • FIG. 1 is a graph showing the therapeutic effect of an external preparation of leflunomide in Test Example 1 on non-injected feet in adjuvant arthritis.
  • FIG. 2 is a graph showing the therapeutic effect of an external preparation of leflunomide of Test Example 1 on an injected foot in adjuvant arthritis.
  • FIG. 3 is a graph showing the therapeutic effect of an external preparation of leflunomide in Test Example 2 on non-injected feet in adjuvant arthritis.
  • FIG. 4 is a graph showing the therapeutic effect of an external preparation of leflunomide in Test Example 2 on an injected foot in adjuvant arthritis.
  • FIG. 5 is a graph showing the therapeutic effect of an external preparation of leflunomide of Test Example 3 on non-injected feet in adjuvant arthritis.
  • FIG. 6 is a graph showing the therapeutic effect of an external preparation of leflunomide of Test Example 3 on an injected foot in adjuvant arthritis.
  • FIG. 7 is a graph showing the effect of the topical leflunomide preparation of Test Example 3 on weight change in adjuvant arthritis.
  • FIG. 8 is a graph showing the therapeutic effect of the topical leflunomide preparation of Test Example 4 on non-injected feet in adjuvant arthritis.
  • FIG. 9 is a graph showing the therapeutic effect of an external preparation of leflunomide of Test Example 4 on an injected foot in adjuvant arthritis.
  • FIG. 10 is a graph showing the change in serum concentration when the topical leflunomide preparation of Test Example 5 was transdermally administered.
  • the active ingredient of the pharmaceutical composition for transdermal administration of the present invention is N- (4-trifluoromethylphenyl) -15-methylisoxazole-4-carboxamide (hereinafter abbreviated as leflunomide in the present specification). Or an active metabolite thereof or a pharmacologically acceptable salt thereof.
  • the active metabolite of N- (4-trifluoromethylphenyl) -1-5-methylisoxazolyl-4-carboxamide is N- (4-trifluoromethylphenyl) 1-2-cyano 1-hydroxyhydroxy tonamide (hereinafter sometimes abbreviated as leflunomide metabolite in the present specification).
  • the pharmacologically acceptable salts of the active metabolites include, for example, alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium, and organic ammonium salts such as ammonia, triethylamine and pyridine. Is mentioned.
  • the pharmaceutical composition for transdermal administration of the present invention comprises leflunomide, a metabolite of leflunomide or a pharmacologically acceptable salt thereof, which is an active ingredient (hereinafter referred to as leflunomide in the present specification, including both). ) Is contained in a carrier containing a specific base, whereby the active ingredient can be stably retained. As a result, the absorption is enhanced, and the intended anti-inflammatory effect or anti-rheumatic effect is markedly improved.
  • the amount of leflunomide contained as an active ingredient in the pharmaceutical composition for transdermal administration of the present invention is 0.1 to 10 w / w%, preferably 0.1 to 1 w / w% based on the total amount of the agent. It is selected from the range of 0 w / w%. More preferably, it is selected from the range of 0.2 to 5 wZw%, and further preferably, it is selected from the range of 1 to 5 w / w%.
  • Leflunomides which are the active ingredients of the pharmaceutical composition for transdermal administration of the present invention, vary greatly in physicochemical properties such as solubility and stability depending on the selected base. If the active ingredient is not kept physicochemically stable in the carrier containing the selected base ingredients, it may have a significant effect on not only the formulation stability but also the absorption and efficacy of the active ingredient There is.
  • the “carrier for transdermal administration” refers to a component obtained by removing the active ingredient leflunomide from the pharmaceutical composition for transdermal administration of the present invention.
  • the carrier for transdermal administration of the present invention contains a “dissolution base” or a “suspension base that is hydrophobic and has no polar group in the molecule”.
  • the pharmaceutical composition for transdermal administration of the present invention when a dissolution base is used, becomes a “solution-type pharmaceutical composition for transdermal administration” in which the active ingredient is dissolved, and is hydrophobic and has an intramolecular structure.
  • a suspension base having no polar group When a suspension base having no polar group is used, a "suspension-type transdermal pharmaceutical composition" in which the active ingredient is suspended is obtained.
  • the “dissolution base” used as a component of the transdermal administration carrier in the “soluble pharmaceutical composition for transdermal administration” of the present invention refers to the active ingredient leflunomide in a formulation in a dissolved state. It is a base for percutaneously absorbing leflunomides.
  • the dissolving base include one or more mixtures selected from dialkyl dibasic acid esters, polyoxyethylene polyoxypropylene glycol, medium-chain fatty acid triglycerides, and macrogol.
  • dialkyl dibasic acid ester can be selected from pharmacologically acceptable ones. Specific examples include getyl sebacate, disopropyl sebacate, diisopropyl adipate, disobutyl adipate and the like. Preferred are, for example, getyl sebacate or diisopropyl adipate. They are generally used as excipients in pharmaceutical preparations and are commercially available from various manufacturers.
  • Polyoxyethylene polyoxypropylene glycol can be appropriately selected from pharmacologically acceptable ones. Specifically, for example, polyoxyethylene (20) polyoxypropylene (20) glycol, polyoxyethylene (3) polyoxypropylene (17) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene Ethylene (54) Polypropylene (39) glycol, polyoxyethylene (120) Polyoxypropylene (40) glycol, polyoxyethylene (160) Polyoxypropylene (30) glycol, polyoxyethylene (196) Polyoxypropylene (67 ) Glycol and the like. Preferred are those which exhibit a liquid state at 30 ° C.
  • polyoxyethylene (20) polyoxypropylene (20) glycol or polyoxyethylene (3) polyoxypropylene (17) glycol Is mentioned.
  • Particularly preferred are polyoxyethylene (20) polyoxypropylene (20) glycol. These are generally used as excipients in pharmaceutical preparations and are commercially available from various manufacturers.
  • “Medium chain fatty acid triglyceride” can be appropriately selected from those pharmacologically acceptable.
  • Examples of the “medium chain fatty acid triglyceride” include glycerin triesters composed of fatty acids having 8 to 12 carbon atoms.
  • fatty acid triglyceride having a single chain length such as glycerin tri-prylate, glycerin triisooctanoate, glycerin trinonanoate, glycerin tri-potrate, glycerin tridecanoate, and glycerin trilaurate, as well as mixed Examples of fatty acid esters such as triglycerin (caprylic acid, hydrauric acid) and glycerin tri (caprylic acid, hydrauric acid, lauric acid) can be given.
  • Preferable examples include triglycerides of mixed fatty acids composed of fatty acids having 8 to 12 carbon atoms. More preferred are mixed fatty acid-type triglycerides composed of fatty acids having 8 to 10 carbon atoms in view of melting point and solubility. These are generally used as excipients for pharmaceutical preparations and are commercially available from various manufacturers.
  • Microgol polyethylene glycols
  • Those that show a liquid state in C are listed.
  • macro goal 200, 300, or 400 or the like can be mentioned.
  • Each of the above dissolving bases can be used alone or as a mixture.
  • dibasic acid dialkyl ester or polyoxyethylenepolyoxypropylene glycol as the first dissolution base. More preferred are dibasic acid dialkyl esters, and particularly preferred are getyl sebacate or diisopropyl adipate.
  • the content of the base for dissolution in the carrier for transdermal administration in the soluble pharmaceutical composition for transdermal administration of the present invention is at least 40 w / w%, preferably 50 w / w% or more in the carrier. It is more preferably at least 60 wZw%.
  • the content of the base for dissolution is less than 40 w / w%, the stability of dissolution of the active ingredient leflunomide in the carrier for transdermal administration is reduced, and as a result, the desired medicinal effect is obtained. There is a risk that it will not be available.
  • the dissolved state of the active ingredient is sufficiently maintained, and the stability as a soluble pharmaceutical composition for transdermal administration is improved. Since it is excellent and the percutaneous absorption of the active ingredient is enhanced, it is possible to exhibit excellent medicinal effects.
  • leflunomide which is an active ingredient in the pharmaceutical composition for transdermal administration of the present invention, has a property of hardly dissolving in hydrocarbon oil. Permission in carriers for transdermal administration If hydrocarbon oils are included in excess of that allowed, the solubility of leflunomides will drop sharply. As a result, in the case of the soluble pharmaceutical composition for transdermal administration of the present invention, leflunomide may precipitate or crystallize during storage. When the content of leflunomide is high, phase separation may occur with the base for dissolution due to solubility problems. For this reason, it is not preferable to include a certain amount or more of hydrocarbon oil as a component of the carrier in the carrier for transdermal administration in terms of formulation stability and efficacy.
  • the content when using a hydrocarbon oil as one of the base components used in a carrier for transdermal administration, the content should be 40 w / w% or less, and should not exceed the content of the dissolution base. It is desirable to do so.
  • Hydrocarbon oils include non-polar oils composed of carbon and hydrogen atoms. Specifically, for example, liquid paraffin, n-paraffin, iso-paraffin, gelled hydrocarbon, polybutene, vaseline, white cellulose, solid paraffin, petroleum hydrocarbons such as microcrystalline sugar, squalane squalene, etc. And animal and plant hydrocarbon oils.
  • a transdermal absorption enhancer is added as a component of the carrier for transdermal administration, in addition to the above-mentioned base component for dissolution, as long as the dissolution state of the active ingredient is not impaired. Can also be used.
  • transdermal absorption enhancer examples include fatty acids such as lauric acid, oleic acid and isostearic acid, higher alcohols such as lauryl alcohol, oleyl alcohol and isostearyl alcohol, lipophilic nonionic surfactants, or 1 —Menthyl, 1-limonene, d-limonene, d1-limonene or other essential oils, and other known absorption promoters, etc., which can be used according to the purpose.
  • fatty acids such as lauric acid, oleic acid and isostearic acid
  • higher alcohols such as lauryl alcohol, oleyl alcohol and isostearyl alcohol
  • lipophilic nonionic surfactants or 1 —Menthyl, 1-limonene, d-limonene, d1-limonene or other essential oils, and other known absorption promoters, etc., which can be used according to the purpose.
  • the solubility of leflunomide as an active ingredient is not impaired,
  • the absorptivity at the surface can be improved, and the Jie effect can be further enhanced.
  • the lipophilic nonionic surfactant examples include poly-monoalkylglycerol esters, glycerin monofatty acid esters, polyglycerin fatty acid esters, and sorbin fatty acid esters.
  • Specific examples of the mono-alkyl glyceryl ether include, for example, ⁇ -monodyl glyceryl ether, mono-tridecyl glyceryl ether, ⁇ -mono-myristyl glyceryl ether, and mono-monopentyl decyl glyceryl Ether, mono-monocetyl glyceryl ether, mono-stearyl glyceryl ether, ⁇ -monoisostearyl glyceryl ether, mono-monooleyl glyceryl ether and the like.
  • Preferred are those having a relatively low melting point and become liquid on the skin, and specific examples thereof include ⁇ -monoisostearyl glyceryl
  • glycerin monofatty acid ester examples include, for example, glycerin monolaurate, glycerin monotridecanoate, glycerin monomyristate, glycerin monodecanoate, glycerin monopalmitate, glyceryl monostearate, Glyceryl monoisostearate, glyceryl monooleate and the like can be mentioned.
  • preferred are those which have a relatively low melting point and become liquid on the skin, and specific examples include glycerin monoisostearate and glyceryl monooleate.
  • polyglycerin fatty acid ester examples include, for example, lauric acid, tridecanoic acid, myristic acid, aminodecanoic acid, palmitic acid, stearic acid, isostearic acid, and oleic acid, similar to the above-mentioned glycerin fatty acid esters.
  • Esters of acid and polyglycerin are mentioned.
  • polyglycerin examples include diglycerin, triglycerin, tetraglycerin, hexaglycerin, decaglycerin and the like.
  • sorbitan fatty acid esters include, for example, sorbitan monolaurate, sorbitan dilaurate, sorbitan monomyristate, sorbitan dimyristate, sorbitan monopalmitate, Examples thereof include sorbitan palmitate, sorbitan monostearate, sorbitan distearate, sorbitan monoisostearate, sorbitan diisostearate, sorbitan monooleate, and sorbitan dioleate.
  • polyglycerin S fatty acid esters and sorbic acid fatty acid esters preferred are those which have a relatively low melting point and become liquid on the skin, and specifically, for example, isostearin Acid esters or oleic acid esters.
  • Preferred examples of the lipophilic nonionic surfactant include mono-alkyl glyceryl ethers, and more preferred examples thereof include mono-isoisoaryl glyceryl ether.
  • the content of the lipophilic nonionic surfactant in the carrier for transdermal administration is selected from the range of 0.1 to 10 wZw%. You. Preferably it is selected from the range of 0.2-5 w / w%, more preferably from the range of 0.5-3 w / w%.
  • the resulting pharmaceutical composition for transdermal administration may have reduced stability.
  • the amount of leflunomide contained as an active ingredient in the pharmaceutical composition for transdermal administration according to the present invention is 0.01 to 10 wZw%, preferably 0.1 to 10%, based on the total amount of the agent. It is selected from the range of 10 wZw%. More preferably, it is selected from the range of 0.2 to 5 w / w%, and further preferably, it is selected from the range of 1 to 5 w / w%.
  • the final pharmaceutical form of the soluble pharmaceutical composition for transdermal administration containing leflunomide as an active ingredient according to the present invention includes, for example, ointments and liquid preparations from those conventionally used as external preparations , Gel preparations, patches and the like.
  • External preparations of these dosage forms can be produced by an ordinary method using an ordinary base or a thickener. These can be produced, for example, according to the descriptions in the “Transdermal Application Formulation Development Manual” edited by Mitsuo Matsumoto (1985), Japanese Patent No. 2651616, W096 / 12465, Japanese Patent Application Laid-Open No. 9-27851, etc. it can.
  • the ointment examples include oily ointment, hydrophilic ointment and the like.
  • the components used in the carrier for transdermal administration are selected according to each drug.
  • the base for dissolution is selected from, for example, dialkyl dibasic acid esters and triglycerides of medium-chain fatty acids, and mixtures thereof.
  • dialkyl dibasic acid esters such as getyl sebacate and diisopropyl adipate and triglycerides of medium chain fatty acid triglyceride (force prillic acid and force pric acid) glycerin.
  • fatty oils such as vegetable oils and animal oils, fatty acid esters, fatty alcohols, and polyalkylenes
  • glycols those generally known as bases for ointments such as hydrocarbon oils can be appropriately selected and blended.
  • the oily ointment may be prepared by thickening a carrier for transdermal administration as a dissolution base or, if necessary, a base mixture in which the above components are appropriately added to the dissolution base.
  • the dissolution base is selected from, for example, polyoxyethylene polyoxypropylene glycol-macrogol (polyethylene glycol) and the like, and a mixture thereof.
  • polyoxyethylene polyoxypropylene glycol-macrogol polyethylene glycol
  • polyoxyethylene glycol polypropylene glycol
  • polyoxyethylene (3) polyoxypropylene (17) glycol
  • polyoxyethylene (42) polyoxypropylene Pyrene (67) glycol
  • glycol polyoxyethylene (120) polyoxypropylene (40)
  • polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, macrogol 200, Macro Goals such as Macro Goal 300, Macro Goal 400, Macro Goal 150, Macro Goal 150, Macro Goal 400, Macro Goal 200 0 0, etc.
  • Macro Goals such as Macro Goal 300, Macro Goal 400, Macro Goal 150, Macro Goal 150, Macro Goal 400, Macro Goal 200 0 0, etc.
  • alcohols such as propylene glycol, povidone, and polyvinyl alcohol are highly soluble in water as long as the solubility and stability of the active ingredient leflunomides are not impaired.
  • dissolving bases such as molecules, dialkyl dibasic acid esters such as dimethyl sebacate / diisopropyl isopropyl adipate, and other dissolving bases such as triglycerides of medium-chain fatty acids, and mixtures thereof can also be blended.
  • Examples of the solution include an oil-based solution and a hydrophilic solution.
  • the dissolving base may be, for example, dibasic dialkyl esters such as getyl sebacate and diisopropyl adipate, medium chain fatty acid triglycerides such as tri (capryl-capric acid) glycerin and the like. Selected from a mixture of
  • Carriers for transdermal administration that are used in oily dissolving solutions include dibasic dialkyl esters such as ethyl sebacate and diisopropyl adipate, and medium-chain fatty acid triglycerides such as tri (capryl'potrimic acid) glycerin.
  • dibasic dialkyl esters such as ethyl sebacate and diisopropyl adipate
  • medium-chain fatty acid triglycerides such as tri (capryl'potrimic acid) glycerin.
  • fatty oils such as vegetable oils and animal oils, fatty acid esters, fatty alcohols, and polyolefins, as long as the solubility and stability of the active ingredient leflunomide are not hindered.
  • fatty oils such as vegetable oils and animal oils, fatty acid esters, fatty alcohols, and polyolefins, as long as the solubility and stability of the active ingredient leflunomide are not hindered.
  • alkylene glycols and the like liquid ones and mixtures thereof can also be blended. Specifically, for example, isopropyl myristate, octyldodecyl myristate, oleyl oleate, decyl oleate, isostearic acid, oleyl alcohol, liquid lanolin, Examples include kinetic paraffin, squalane, squalene, polybutene, silicone oil and the like, and mixtures thereof.
  • the dissolving base is selected from, for example, polyoxyethylenepolyoxypropyleneglycols, macgol and the like, and mixtures thereof.
  • the solubility and stability of the active ingredient leflunomide are not impaired, in addition to the dissolution base, as a component of the carrier for transdermal administration, for example, alcohols such as propylene glycol and mixtures thereof are mixed. You can also.
  • Gel formulations include oily gels and aqueous gels.
  • the base for dissolving is, for example, dialkyl dibasic acid esters such as getyl sebacate and diisopropyl adipate, medium chain fatty acid triglycerides such as tri (force prill 'force pric acid) glycerin, and mixtures thereof. Is selected from
  • a component of a carrier for transdermal administration other than a dissolving base as long as the solubility and stability of the active ingredient leflunomide are not hindered for example, fatty oils such as vegetable oils and animal oils, fatty acid esters, and fatty alcohols , A polyalkylene glycol, or the like, a liquid one can be used in combination with the above-mentioned dissolving base as needed.
  • the oil-based gel preparation is used as a component of another carrier for transdermal administration and a component for gelling or thickening the dissolving base or the base mixture containing the dissolving base. It is prepared by blending.
  • the component for gelling or thickening for example, polymer compounds ⁇ metal stones such as aluminum stearate ⁇ , inorganic salts, purified organic clays such as hectorites and the like, and mixtures thereof can be used.
  • the dissolving base is selected from, for example, polyoxyethylene polyoxypropylene glycols, macmouths and the like, and mixtures thereof.
  • alcohols such as propylene glycol may be used as a component of the carrier for transdermal administration other than the dissolving base. It can be used in combination with an agent as needed.
  • Aqueous gel preparations are prepared by blending these dissolving bases or base mixtures containing the dissolving bases with components for the transdermal administration carrier and for further gelling or thickening them. Be prepared.
  • a component for gelling or thickening for example, an aqueous polymer such as carboxymethyl polymer, hydroxypropyl cellulose, or polyvinyl alcohol can be blended.
  • a dosage form such as a patch can be further selected.
  • the patch is obtained by laminating an adhesive plaster on a support.
  • a flexible material that can freely follow the expansion and contraction of the skin is preferable.
  • known films such as polyethylene, polyethylene terephthalate, plastic films such as polypropylene, non-woven cloth, cloth, paper, etc. Things.
  • the plaster of the patch consists of a base for dissolution and an adhesive or, if necessary, a tackifier and a softener added, taking into account skin safety, adhesion to the skin, etc. Can be appropriately selected from known ones.
  • dissolving base used in the patch examples include dibasic acid dialkyl esters such as getyl sebacate and diisopropyl adipate, medium-chain fatty acid triglycerides such as triglyceride (capril and capric acid), and the like. Their mixture is selected.
  • the pressure-sensitive adhesive can be selected from, for example, acrylic, rubber, silicone and the like.
  • examples of the acrylic type include (co) polymers mainly composed of alkyl (meth) acrylate. This (co) polymer is composed of two or more
  • Copolymers of (meth) alkyl acrylates may be used. It may be a copolymer of a functional monomer copolymerizable with an alkyl acrylate and an alkyl (meth) acrylate.
  • Rubber-based adhesives include, for example, rubber adhesives such as natural rubber, polyisopropylene rubber, polyisobutylene rubber, styrene-isoprene-styrene block copolymer, and styrene-butylene-styrene-styrene copolymer.
  • silicone type examples include those containing a silicone rubber as a main component, such as polydimethylsiloxane and diphenylsiloxane.
  • tackifier examples include rosin, hydrogenated rosin, rosin ester, hydrogenated rosin ester, polyterpene resin, and oil-soluble phenol resin.
  • the softening agent plasticizes and softens the above-mentioned pressure-sensitive adhesive and tackifier to maintain proper adhesion to the skin, and includes, for example, almond oil, olive oil, ebaki oil, persic oil, laccase oil, and olefin. Acids, liquid paraffin and the like can be used.
  • the thickness of the plaster laminated on the support is selected in the range of 1 to 100 111, and preferably in the range of 100 to 500 zm. More preferably
  • It is selected from the range of 20 to 200 m.
  • the amount of leflunomide contained as an active ingredient in ointments, solutions, gel preparations, and patches is selected from the range of 0.01 to 10 wZw% based on the total amount of the preparation, and is preferably It is selected from the range of 0.1 to 10 wZw%. More preferably ⁇ .
  • It is selected from the range of 2-5 w / w%, and more preferably selected from the range of 1-5 w / w%.
  • additives may be added to these ointments, solutions, gelling agents, and patches, as desired, as a component of a carrier for transdermal administration within a range not to impair the purpose of the present invention.
  • Ingredients such as fragrances, fillers, wetting agents, stabilizers, preservatives, or emulsifiers can also be incorporated.
  • wetting agent examples include propylene glycol, glycerin, 1,3-butylene glycol and the like.
  • examples of the stabilizer include dibutylhydroxytoluene, dl-a-tocopherol, tocopherol acetate, propyl gallate and the like.
  • preservative examples include methyl paraben, ethyl paraben, propyl paraben, chlorobutanol, benzyl alcohol and the like.
  • the emulsifier can be appropriately selected from those generally used in pharmaceuticals, and specifically includes, for example, sucrose fatty acid esters, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monoolate, and polyoxyethylene.
  • Polysorbates such as ethylene sorbitan trioleate, polyoxyethylene alkyl ethers such as polyoxyethylene styrene, polyoxyethylene alkyl ethers, etc.
  • xishylene fatty acid esters such as ethylene sorbitan trioleate, polyoxyethylene alkyl ethers such as polyoxyethylene styrene, polyoxyethylene alkyl ethers, etc.
  • xishylene fatty acid esters such as xishylene fatty acid esters.
  • the soluble pharmaceutical composition for transdermal administration of the present invention is prepared by dissolving leflunomide as an active ingredient in a specific dissolution base. Specifically, for example, leflunomides are added to a dissolution base and sufficiently dissolved. Depending on the dosage form selected, various bases and additives are added to form ointments, solutions, gel preparations, and the like. Preparation conditions such as temperature and stirring power may be selected from conditions suitable for each dosage form. Normally, ointments should be in the range from around room temperature to about 80 ° C, liquids should be in the range from around room temperature to about 50 ° C, and gels should be at room temperature. It is prepared within a range from around 60 ° C.
  • a patch for example, after adding leflunomide to the dissolution base and dissolving it sufficiently, this is then added to the adhesive as described above or, if necessary, further tackified. It is prepared by laminating a plaster prepared by mixing an agent and a softener on a support such as a plastic film.
  • the method for preparing the patch include a hot melt method and a solvent method, and may be appropriately selected and prepared according to the purpose.
  • the temperature ranges from about 150 ° C to about 250 ° C, and in the case of the solvent method, for example, in the case of hexane.
  • Examples of the dosage form of the pharmaceutical composition for transdermal administration according to the present invention include ointments, liquid preparations, gel preparations, patches and the like. Of these, ointments, liquids and patches are preferred. Particularly preferred are solutions or patches.
  • the pharmaceutical composition for transdermal administration of the present invention can stably dissolve leflunomide as an active ingredient, and as a result, exhibits excellent absorption and drug efficacy Can be done.
  • the pharmaceutical composition for transdermal administration of the soluble type of the present invention has the advantages that the uniformity of the content of the active ingredient is easily ensured and the production is easy.
  • the suspension-type pharmaceutical composition for transdermal administration of the present invention contains leflunomide as an active ingredient in a suspended state.
  • the carrier for transdermal administration is selected from one or more suspension bases which are hydrophobic and have no polar group in the molecule, or It consists of a mixture of these suspending bases and other components required for formulation.
  • leflunomides have a weak affinity for various polar group-containing substances, regardless of their hydrophilicity or hydrophobicity. When a substance having the following is contained, the solubility of leflunomide is improved, and as a result, undesired morphological changes such as crystal growth and phase separation occur during storage.
  • polar group specifically refers to, for example, a hydroxyl group, a carboxy group, a carbonyl group, an amino group, an amine group, an ammonium group, a halogen group, an acidic group (for example, a sulfonyl group, Group) and various metal salts.
  • the suspending base that is hydrophobic and does not have a polar group in the molecule used in the “transdermal carrier” can be selected from various pharmacologically acceptable bases. In consideration of the solubility characteristics and stability of flunomids, it is preferable to select a hydrocarbon oil, and more preferably a hydrocarbon oil.
  • hydrocarbon oil examples include petrolatum, white petrolatum, refined petrolatum, n-paraffin, isoparaffin, liquid paraffin, gelled hydrocarbon, microChristmas phosphorus, squalane, squalene, polybutene, polyisoprene, and the like. Preferred are gelled hydrocarbons. “Gelled hydrocarbons” are obtained by gelling heavy liquid paraffin, which is a liquid hydrocarbon oil, with polyethylene, and are commercially available as PLASTIBASE (registered trademark).
  • the content of the “hydrophobic suspension base having no polar group in the molecule” used in the “carrier for transdermal administration” in the suspension-type pharmaceutical composition for transdermal administration of the present invention is as follows.
  • the carrier is selected from a range of 70 wZw% or more, preferably 80 wZw% or more, more preferably 9 OwZw% or more, and particularly preferably 95 w / w% or more with respect to the carrier.
  • Suspension-type pharmaceutical compositions for transdermal administration that are particularly excellent in the stability of leflunomides by selecting a carrier whose main component is "a suspension base that is hydrophobic and has no polar group in the molecule.” Can be prepared.
  • the shape of leflunomide as an active ingredient used in the suspension-type pharmaceutical composition for transdermal administration of the present invention is not particularly limited.
  • a suspension-type preparation is prepared, the primary particles of the dispersion are not crushed.
  • leflunomides to be suspended in the carrier for transdermal administration of the present invention have a particle diameter of 100 zm or less. It is preferable to choose one.
  • a particle having substantially all particles having a particle diameter of 100 m or less and an average particle diameter of 20 zm or less is selected. More preferably, a particle having substantially all particles having a particle diameter of 20 zm or less and an average particle diameter of 10 m or less is selected. If the particle size of the active ingredient exceeds 100 m, the uniformity and transdermal absorption of the finally obtained pharmaceutical composition may be impaired.
  • Substantially all particles are 100 zm or less or 20 zm or less.
  • 90% or more of all particles are 100 m or less or 20 zm.
  • the particles have the following particle size distribution.
  • the average particle diameter means an average volume diameter.
  • the average particle size and the particle size distribution are measured by a laser-diffraction type particle size distribution measuring device, and the specific measuring method is as described in Examples.
  • the active ingredient is pulverized using a jet mill or the like.
  • leflunomides contained as an active ingredient are stably suspended in a carrier for transdermal administration.
  • the content can be selected from a wide range without considering the solubility of leflunomides and the like.
  • the amount of leflunomide contained as an active ingredient in the suspension-type transdermal pharmaceutical composition of the present invention is, specifically, 0.01 to 20 w / w with respect to the total amount of the composition.
  • w / w% preferably from 0.1 to 10 w / w%. More preferably, it is selected from the range of 0.5 to 10 w / w%, and further preferably, it is selected from the range of 1 to 5 w / w%.
  • a dosage form conventionally used as an external preparation may be used as a ⁇ suspension which is hydrophobic and has no polar group in the molecule ''.
  • ⁇ suspension which is hydrophobic and has no polar group in the molecule ''.
  • ⁇ base hydrophobic and has no polar group in the molecule ''.
  • ointments, liquids, patches, etc. External preparations of these dosage forms are manufactured by a usual method using a usual base or thickener can do. These can be produced, for example, according to the descriptions in the “Transdermal Application Formulation Development Manual” edited by Mitsuo Matsumoto (1985), Japanese Patent No. 2651616, W096 / 12465, Japanese Patent Application Laid-Open No. 9-27851, etc. it can.
  • Ointments include, for example, oily suspension ointments.
  • Examples of the “suspension base that is hydrophobic and has no polar group in the molecule” used in oily suspension ointments include, for example, petrolatum, white petrolatum, purified petrolatum, paraffin, liquid paraffin, and hydrocarbons. And a suspension base having no polar group, such as gelled hydrocarbon, squalene, squalane, and polybutene.
  • fatty oils such as vegetable oils and animal oils, fatty acid esters, aliphatic alcohols, polyalkylene glycols, etc.
  • fatty acid esters such as vegetable oils and animal oils
  • fatty acid esters such as fatty acid esters, aliphatic alcohols, polyalkylene glycols, etc.
  • Examples of the components other than the “hydrophobic suspension base having no polar group in the molecule” which can be used in the suspension-type pharmaceutical composition for transdermal administration of the present invention include lanolin and liquid lanolin , Purified lanolin, beeswax, salami beeswax, getyl sebacate, disopropyl adipate and triglyceride, a medium-chain fatty acid triglyceride, Glycerin, butyldecyl stearate, hexadecyl isostearate, isopropyl palmitate, isostearyl palmitate, isopiryl myristate, oral pill, octyldodecyl myristate, cetyl myristate, oleyl oleate, decyl oleate, tritriate
  • Examples include glycerin myristate, castor oil, hardened oil, glycerin monostearate, stea
  • the content of components other than the above-mentioned “hydrophobic base material having no polar group” does not exceed 30 w / w% with respect to the carrier.
  • suspension examples include an oily suspension, and a base to be used as a carrier is selected according to the purpose as in the above-mentioned ointment.
  • the “suspension base that is hydrophobic and has no polar group in the molecule” used in oily suspensions has, for example, a polar group such as liquid paraffin, hydrocarbon, squalene, squalane, or polybutene. Select a suspension base that does not contain any liquid. Further, other components, such as fatty oils such as vegetable oils and animal oils, fatty acid esters, fatty alcohols, and polyalkylene glycols, as long as the suspension and stability of the active ingredient leflunomide are not impaired. Liquid bases can be appropriately selected from those generally known as bases for ointments, and used.
  • Components other than the “hydrophobic suspension base having no polar group in the molecule” that can be used in an oily suspension include, specifically, for example, ethyl sebacate, adipine Medium-chain fatty acid triglyceride such as diisopropyl acid, tri (caprylic acid, hydropric acid) glycerin, isopropyl myristate, octyldodecyl myristate, oleyl oleate, decyl oleate, glycerin trimyristate, castor oil, isostearic acid, Oleyl alcohol, silicone oil, etc.
  • ethyl sebacate such as diisopropyl acid, tri (caprylic acid, hydropric acid) glycerin, isopropyl myristate, octyldodecyl myristate, oleyl oleate, decyl oleate, g
  • the suspension-type patch is obtained by laminating an adhesive plaster using “a suspension base that is hydrophobic and has no polar group in the molecule” on a support.
  • a support a flexible material that can freely follow the expansion and contraction of the skin is preferable, and examples thereof include known materials such as plastic films such as polyethylene, polyethylene terephthalate, and polypropylene, nonwoven fabrics, cloths, and papers.
  • the plaster constituting the patch is composed of a suspending base and an adhesive or, if necessary, a tackifier and a softener, and is used to improve skin safety and adhesion to the skin. It can be selected from known ones in a timely manner.
  • Examples of the “suspension base that is hydrophobic and does not have a polar group in the molecule” used in the patch include petrolatum, white petrolatum, purified petrolatum, paraffin, liquid paraffin, hydrocarbon, gelation Hydrocarbons, squalene, squalane, polybutene, etc. are selected.
  • the pressure-sensitive adhesive can be selected from, for example, acrylic, rubber, silicone and the like.
  • examples of the acrylic type include (co) polymers mainly composed of alkyl (meth) acrylate. This (co) polymer is composed of two or more
  • It may be a copolymer of (meth) alkyl acrylate, or a copolymer of (meth) functional monomer copolymerizable with alkyl acrylate and (meth) alkyl acrylate. There may be.
  • Examples of the rubber-based rubber include those mainly containing a rubber adhesive such as natural rubber, polyisopropylene rubber, polyisobutylene rubber, styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer.
  • a rubber adhesive such as natural rubber, polyisopropylene rubber, polyisobutylene rubber, styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer.
  • Can be Examples of the silicone type include those based on silicone rubber such as polydimethylsiloxane and diphenylsiloxane.
  • tackifier examples include rosin, hydrogenated rosin, rosin ester, hydrogenated rosin ester, polyterpene resin, and oil-soluble phenol resin.
  • the thickness of the plaster laminated on the support is selected in the range of 1 to 100 / m, preferably in the range of 100 to 500 m. More preferably, it is selected from the range of 20 to 20.
  • lipophilic nonionic surfactant examples include, for example, sorbitan esters of sorbitan such as sorbitan monostearate, sorbitan monopalmitate, sorbitan monooleate, and sorbitan sesquioleate; Glycerin fatty acid esters such as glyceryl monostearate, glyceryl monoisostearate, and glyceryl monooleate; mono-alkyl glyceryl ethers such as batyl alcohol, seracyl alcohol, and monoisostearyl glyceryl ether; sucrose fatty acid esters Polysorbates such as polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan trioleate, polyoxyethylene cetyl ether, poly Carboxymethyl ethylene O rail E poly O key Chez Ji alkylene alkyl ethers single ether such as polyoxyl stearate, and the like polio Kishi
  • the addition of these lipophilic nonionic surfactants has the effect of improving the affinity for the skin.
  • an ointment is particularly preferred.
  • the suspension-type pharmaceutical composition for transdermal administration containing leflunomide of the present invention is made into an ointment having an appropriate consistency so that the dispersion stability of leflunomide suspended in carrier as an active ingredient is improved. In addition to being retained, it can remain on the skin for a long time after administration, and as a result, excellent drug efficacy can be exhibited.
  • the amount of leflunomide contained as an active ingredient in the above-mentioned ointment, liquid preparation or patch is selected from the range of 0.01 to 2 OwZw, preferably 0. It is selected from the range of 1 to 1 O w / w%. More preferably 0. It is selected from the range of 2 to 10 wZw%, and more preferably selected from the range of 1 to 5 wZw%.
  • the suspension-type medical vegetable composition for transdermal administration of the present invention is prepared by suspending and dispersing leflunomide as an active ingredient in a specific suspension base. Specifically, for example, a sufficiently pulverized raw powder of leflunomide is added to a suspension base and stirred sufficiently. After that, various bases and additives are added according to the selected dosage form to form ointments, liquids and the like. Preparation conditions such as temperature and stirring power may be selected from conditions suitable for each dosage form. However, excessive heating may change the crystalline state of leflunomide suspended in the carrier as an active ingredient.For example, adjust the temperature from around room temperature to about 50 ° C. It is desirable to do.
  • An ointment can be prepared at around room temperature by using, for example, a rotation-revolving mixer (Awatori Nerita AR-250, manufactured by Shinky Corporation). It can also be prepared by sufficiently stirring while controlling the temperature using a vacuum emulsifier or the like.
  • a suspension patch for example, after adding a sufficiently pulverized raw powder of leflunomide into a suspension base and stirring sufficiently to suspend and disperse, Is prepared by laminating a paste prepared by mixing an adhesive or, if necessary, a tackifier and a softener as described above on a support such as a plastic film.
  • a method for preparing a patch include a hot melt method and a solvent method, and the preparation may be appropriately selected and prepared according to the purpose.
  • Preparation conditions such as temperature may be selected from conditions suitable for each preparation method. However, excessive heating may change the crystalline state of leflunomides suspended in the carrier as an active ingredient.For example, use a solvent method to reduce the temperature from around room temperature to 50 ° C. It is desirable to prepare it in the range up to about.
  • the disease to be treated is not particularly limited. Excellent for treating rheumatoid arthritis or arthritis.
  • the site of administration may be applied to any site as long as it is on the skin, but is preferably applied to the skin at or near the affected area.
  • the dose is appropriately selected depending on the age, weight, sex, symptoms, dosage form, and administration site of the patient. Usually, for adults, the dose of leflunomide is lmg to: LOg / day.
  • leflunomide pulverized using a jet mill was used to prepare a suspension-type pharmaceutical composition for transdermal administration.
  • this bulk powder was analyzed with a laser diffraction particle size distribution analyzer (SAL D-3000, manufactured by Shimadzu Corporation), the average particle diameter was 7 ⁇ m, and 90% or more of the particles were 20 m. It was included below. (Measurement conditions: dry type, refractive index: 1.70-0.00i)
  • getyl sebacate (trade name: NIKKOL DES-SP, Nikko Chemicals Co., Ltd.) was heated to about 40 ° C., and 1 g of leflunomide was added with stirring. After confirming dissolution, the mixture was cooled to room temperature to obtain a 1% solution A of leflunomide.
  • getyl sebacate (trade name: NIKKOL DES-SP, Nikko Chemicals Co., Ltd.) was heated to about 40 ° C., and 5 g of leflunomide was added with stirring. After confirming dissolution, the mixture was cooled to room temperature to obtain a 5% solution B of leflunomide.
  • Flunomide solution II 5 g of leflunomide was added at room temperature while stirring 95 g of polyoxyethylene (20) polyoxypropylene (20) glycol (trade name: Adecapul Knick L-44, manufactured by Asahi Denka Kogyo KK). After confirming dissolution, a 5% solution D of leflunomide was obtained.
  • Polyoxyethylene (20) polyoxypropylene (20) glycol (trade name: Adecapuru Knick L-44, manufactured by Asahi Denka Kogyo KK) While stirring 9 Og, 10 g of leflunomide was added at room temperature. The dissolution was confirmed, and a 10% solution E of leflunomide was obtained.
  • Getyl sebacate (trade name: NIKKOL DES-SP Nikko Chemicals Co., Ltd.) 55 g and polyoxyethylene (20) polyoxypropylene (20) glycol (trade name: Adecapul Mouth Nick L-44, Asahi Denka Kogyo Co., Ltd.) was mixed at room temperature, and 5 g of leflunomide was added with stirring. After confirming dissolution, a 5% solution F of leflunomide was obtained.
  • Getyl sebacate (trade name: NIKKOL DES-SP, Nikko Chemicals Co., Ltd.) 92.
  • Getyl sebacate (trade name: NIKKOL DES-SP, Nikko Chemicals Co., Ltd.) 40 g :, diisopropyl adipate (trade name: NIKKOL DID, Nikko Chemicals Co., Ltd.) 12 g, polyoxyethylene (20) polyoxy Propylene (20) glycol (trade name: Adecapluronic L-44, manufactured by Asahi Denka Kogyo Co., Ltd.) 30 g, propylene glycol (made by Asahi Denka Kogyo Co., Ltd.) 13 g and ⁇ -monoisoglycol 2.5 g of stearyl glyceryl ether (trade name: Netol GE-IS, manufactured by Kao Corporation) was mixed at room temperature, and 2.5 g of leflunomide was added with stirring. After confirming dissolution, a 2.5% solution K of leflunomide was obtained.
  • isopropyl myristate (trade name: NIKKOL IPM-100, Nikko Chemicals Co., Ltd.) 13 g and monoisostearyl glyceryl ether (Trade name: Venetol GE-IS, manufactured by Kao Corporation) 2.5 g was mixed at room temperature, and 2.5 g of leflunomide was added with stirring. After confirming dissolution, a 2.5% dissolution solution L of leflunomide was obtained.
  • Diisopropyl adipate (trade name: NIKKOL DID, Nikko Chemicals Co., Ltd.) 12 g, polyoxyethylene (20) polyoxypropylene (20) glycol (trade name: Adecapul Mouth Nick L-44, manufactured by Asahi Denka Kogyo Co., Ltd.) ) 53 g, 30 g of propylene glycol (manufactured by Asahi Denka Kogyo Co., Ltd.) and 2.5 g of monoisostearyl glyceryl ether (trade name: Penetol GE-IS, manufactured by Kao Corporation) are mixed at room temperature. While stirring, 2.5 g of leflunomide was added. After confirming dissolution, a 2.5% solution M of leflunomide was obtained.
  • Diisopropyl adipate (trade name: NIKKOL DID, Nikko Chemicals Co., Ltd.) 34.5 g polyoxyethylene (20) polyoxypropylene (20) glycol (trade name: Adekapur Kounik L-44, Asahi Denka Kogyo Co., Ltd.) 30 g, Macrogol 400 (trade name: Macrogol 400, manufactured by Nippon Oil & Fats Co., Ltd.) 27.5 g, a Monomonoyl glyceryl ether (trade name: NIKKOL Seraquil Alcohol, Nikko Chemicals Co., Ltd.) 2.5 g is heated to 40 ° C, mixed, and stirred, and dibutyl hydroxytoluene (trade name: Yoshinox BHT, manufactured by EPI-I-ICO-I CORPORATION) 0.5 g After complete dissolution, an additional 5 g of leflunomide was added. After confirming dissolution, a 5% solution of leflunomide N was obtained.
  • Polyoxyethylene (20) polyoxypropylene (20) glycol (trade name: Adecapuru Knick L-44, manufactured by Asahi Denka Kogyo Co., Ltd.) 50 g, Macrogol 400 (trade name: Macrogol 400, Nihon Yushi ( 10 g, diisopropyl adipate (trade name: NIKKOL DID, Nikko Chemicals Co., Ltd.) and 5 g of leflunomide were mixed and dissolved at room temperature, and heated to about 60 ° C. This was heated to about 70 ° C in advance and melted.
  • Macrogol 4000 (trade name: Macrogol 4000, manufactured by NOF Corporation) and 14 g of stearyl alcohol (trade name: Calcoll 8688, Kao Corporation) ) was slowly added to 11 g of the mixture with stirring. While stirring, the mixture was gradually cooled until it hardened, whereby a 5% dissolved ointment Q of leflunomide was obtained.
  • Macrogol 400 (trade name: Macrogol 400, manufactured by NOF Corporation) and 5 g of leflunomide were mixed and dissolved at room temperature, and heated to about 60 ° C. This was heated to about 60 ° C. in advance and gradually added to 50 g of melted Macrogol 4000 (trade name: Macrogol 4000, manufactured by NOF CORPORATION) with stirring to confirm melting. While stirring, the mixture was gradually cooled until it hardened, whereby an ointment R of 5% dissolution of leflunomide was obtained.
  • getyl sebacate (trade name: NIKKOL DES-SP, Nikko Chemicals Co., Ltd.) was heated to about 40 ° C., and 5 g of leflunomide was added with stirring to confirm dissolution.
  • leflunomide was added 15 g of dimethyldistearylammonium hectrite (trade name: Lucentite SAN, manufactured by Corp Chemical Co., Ltd.), and the mixture was cooled with sufficient stirring to obtain a 5% dissolved gel of leflunomide.
  • Formulation S was obtained.
  • getyl sebacate (trade name: NIKKOL DES-SP, Nikko Chemicals Co., Ltd.) was heated to about 40 ° C., and 2.5 g of leflunomide was added with stirring to confirm dissolution. With further stirring, 2.5 g of monomonoisostearyl glyceryl ether (trade name: Netol GE-IS, manufactured by Kao Corporation) was added and uniformly dissolved to prepare a reflunomide solution.
  • styrene-isoprene-styrene block copolymer (trade name: KRATON D-1107CP, Clayton Polymer Japan Co., Ltd.) 40 g and hydrogenated rosin ester derivative (trade name: Ester Gum H, Arakawa Chemical Co., Ltd.) ))
  • the resulting leflunomide solution was mixed with the dissolved product to obtain a patch T (plaster) having a 2.5% dissolution of leflunomide.
  • getyl sebacate (trade name: NIKKOL DES-SP, Nikko Chemicals Co., Ltd.) was heated to about 40 ° C., and 5 g of leflunomide was added with stirring to confirm dissolution. With further stirring, 2.5 g of monomonoisostearyl glyceryl ether (trade name: Penetol GE-IS, manufactured by Kao Corporation) was added and uniformly dissolved to prepare a leflunomide solution.
  • styrene-isoprene-styrene block copolymer (trade name: KRATON D-1107CP, Clayton Polymer Japan K.K.) 40 g and hydrogenated rosin ester derivative (trade name: Ester Gum H, Arakawa Chemical Industries
  • Plastic base (Product name: Plastic base, manufactured by Bristol Pharmaceutical Co., Ltd.) 9
  • Plastibase brand name Plastibase, Bristol Pharmaceutical Co., Ltd.
  • plastic base brand name: plastic base, Bristol Pharmaceutical Co., Ltd.
  • monoisostearyl glyceryl ether brand name: Netol GE-IS, manufactured by Kao Corporation
  • Leflunomide 5 g was added, and the mixture was sufficiently stirred at room temperature and defoamed to obtain leflunomide 5% suspension ointment d.
  • Leflunomide suspension ointment (5) 85 g of purified petrolatum (trade name: Sun White P-150, manufactured by Nikko Spain Co., Ltd.) and 10 g of isopropyl myristate (trade name: NIKKOL IPM-100, Nikko Chemicals Co., Ltd.) and 5 g of leflunomide are added. Under sufficient stirring, the mixture was defoamed to obtain a leflunomide 5% suspension ointment e.
  • getyl sebacate (trade name: NIKKOL DES-SP, Nikko Chemicals Co., Ltd.) and 5 g of leflunomide were mixed and stirred at 40 ° C. Leflunomide was completely dissolved. While stirring, 60 g of liquid paraffin (manufactured by Yuka Sangyo Co., Ltd.) was further added to obtain Leflunomide 5% solution V.
  • getyl sebacate (trade name: NIKKOL DES-SP, Nikko Chemicals Co., Ltd.) and 5 g of leflunomide were mixed and stirred at 40 ° C. to dissolve leflunomide. With stirring, 45 g of liquid paraffin (manufactured by Yuka Sangyo Co., Ltd.) was added to obtain a 5% solution W of leflunomide.
  • getyl sebacate (trade name: NIKKOL DES-SP, Nikko Chemicals Co., Ltd.) and 5 g of leflunomide were mixed and stirred at room temperature to dissolve leflunomide. Stirring Further, 50 g of squalane (trade name: Super Squalane, manufactured by SQUATEC Co., Ltd.) was further added to obtain a 5% solution X of leflunomide.
  • leflunomide 5 g was added. The mixture was sufficiently stirred at room temperature to obtain a 5% suspension of reflunomide h.
  • Mycobacterium butyricum killed bacterial cells were suspended in liquid paraffin to a concentration of 0.5% in 0.2 ml aliquots under rat anesthesia. It was injected subcutaneously and made. On the 17th day after injection, animals exhibiting edema in the left hind limb were selected and grouped based on the left hind limb volume and body weight. The test substance was applied once a day from the day of grouping for 5 consecutive days. The application area was covered with aluminum foil to prevent rats from licking their limbs. About 5 hours after the final application, the bilateral hind limb volume was measured by the water displacement method, and the difference from the time of grouping was calculated and evaluated.
  • the group composition was as shown in Table 1 below.
  • the external preparation for leflunomide used was the one prepared in the examples, and the preparation blank corresponding to each sample used was the same composition but prepared without leflunomide.
  • Test Example 1 the therapeutic effect of leflunomide external preparations having various compositions on adjuvant arthritis was evaluated.
  • leflunomide shows excellent efficacy when transdermally administered in a specific base.
  • Test Example 1 the therapeutic effect of leflunomide solution having various compositions on adjuvant arthritis was evaluated.
  • the group composition was as shown in Table 5 below.
  • the results are shown in Table 6 and FIGS. Table 7 and FIG. 7 show changes in body weight before and after the test.
  • the leflunomide-containing preparation of the present invention when incorporated in a specific base in a dissolved state, has excellent drug efficacy and also is excellent in safety.
  • Test Example 1 the therapeutic effects of adjuvant arthritis of a leflunomide-dissolving solution having various compositions and a leflunomide-dissolving patch were evaluated.
  • Patch U was applied so as to cover the entire hind limb, and was further fixed with a bandage to prevent the patch from shifting.
  • patch T it was difficult to completely adhere to the hind limb of the rat, so only the plaster excluding the support was administered.
  • Patch U also showed a sufficient edema-suppressing effect as compared to plank, even though patch U could not be completely adhered as a result.
  • the serum concentration of leflunomide in a single administration of the external preparation of leflunomide shown in the example to the adjuvant arthritis plate prepared in the same manner as in Test Example 1 was measured using LC-MSZ MS. At the same time, the serum concentration of a single oral dose of leflunomide (20 mg / kg) was measured and compared.
  • the pharmaceutical composition for transdermal administration of the present invention is a preparation excellent in side effects and sustainability.
  • each of the above samples was placed in a 1 OmL glass screw mouth test tube (NR-10, manufactured by Maruem Co., Ltd.) in a volume of 3 mL, sealed, and stored in a 60 ° C constant temperature bath. At the 3rd and 6th weeks after storage, they were taken out and subjected to liquid chromatography analysis.
  • NR-10 1 OmL glass screw mouth test tube
  • Stability was determined by simultaneously analyzing separately prepared leflunomide standard solutions, and setting the leflunomide peak area value of the standard solution to 100 as the sum of the impurity peak area values of each sample as the relative substance content (%). The evaluation was performed by comparing with the initial value. In addition, this related substance amount includes a peak derived from the base.
  • the dissolving liquids A to P prepared in Examples 1 to 16 and the dissolving liquids V to X prepared in Comparative Examples 1 to 3 were respectively placed in glass screw-mouth test tubes (NR-10, manufactured by Marem Co., Ltd.). Closed and stored in a cool box at 5 ° C, remove them at fixed times after 1, 3, 5, 7, 14, 21, and 28 days, and leave them at room temperature for 2 hours to precipitate crystals. Was visually observed. As a result, none of the dissolving solutions A to P prepared in Examples 1 to 16 showed any precipitation of solids such as crystals.
  • the particle size of the crystals suspended in the carrier did not change even after 6 weeks at 60 ° C.
  • the preparations prepared in Examples 22 and 23 were subjected to a long-term storage stability test to evaluate the stability of the active ingredient.
  • the samples were stored in a refrigerator kept at 5 ° C for 3 days, and the morphology of suspended crystals was observed using an optical microscope for the removed samples. Was compared to what was.
  • suspension-type pharmaceutical composition for transdermal administration of the present invention is a preparation having excellent stability.
  • 0.2 ml of a suspension of dead Mycobacterium butyricum cells (Difco) in liquid paraffin to a concentration of 0.5% was injected subcutaneously into the right hind leg of the rat under 0.2 ml anesthesia. Made by injection. On the 17th day after injection, animals exhibiting edema in the left hind limb were selected and grouped based on the left hind limb volume and body weight. The test substance was applied once a day from the day of grouping for 5 consecutive days. The application area was lightly covered with aluminum foil to prevent rats from licking their limbs. Approximately 5 hours after the final application, the volume of both hind limbs was measured by the water displacement method, and the difference from the time of grouping was calculated and evaluated.
  • Difco dead Mycobacterium butyricum cells
  • the group composition was as shown in Table 15 below.
  • the leflunomide suspension ointment used was the one prepared in the examples, and the formulation blank used was the same composition but without leflunomide. 1385 Table 15 Group composition of evaluation test
  • the pharmaceutical composition for transdermal administration of the present invention containing leflunomide or an active metabolite thereof or a pharmacologically acceptable salt thereof is effective when administered directly to the affected area and to the skin in the vicinity thereof to obtain an effective anti-inflammatory and anti-inflammatory drug. It can show a rheumatic effect.

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Abstract

L'invention concerne une composition médicamenteuse pour administration percutanée, comprenant : a) un ingrédient actif, à savoir, un N-(4-trifluorométhylphényl)-5-méthylisoxazole-4-carboxamide, un métabolite de celui-ci, ou un sel pharmacologiquement acceptable de celui-ci ; et b) (1) un support pour administration percutanée, comprenant au moins 40 % en poids d'une base de dissolution, ou (2) un support pour administration percutanée, comprenant au moins 70 % en poids d'une base de suspension hydrophobe et dépourvue de groupes polaires dans la molécule. La composition constitue un nouveau moyen permettant d'administrer par voie percutanée le flunomide ou un métabolite actif de celui-ci.
PCT/JP2004/011385 2002-02-12 2004-08-02 Composition medicamenteuse pour administration percutanee WO2005011669A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008013494A (ja) * 2006-07-06 2008-01-24 Lintec Corp 経皮吸収貼付剤
DE102014201651A1 (de) 2014-01-30 2015-07-30 Georg-August-Universität Göttingen Stiftung Öffentlichen Rechts, Universitätsmedizin Isoxazolderivate zur Verwendung bei der Behandlung und/oder Prophylaxe von Herzerkrankungen
JP2018504436A (ja) * 2015-02-05 2018-02-15 メモリアル スローン−ケタリング キャンサー センター 浮腫の治療のための組成物及び方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05208909A (ja) * 1991-08-22 1993-08-20 Hoechst Ag 臓器移植における拒絶反応治療用医薬
JPH06329538A (ja) * 1993-03-31 1994-11-29 Hoechst Ag 皮膚疾患処置用薬剤
JPH10158166A (ja) * 1996-12-02 1998-06-16 Taisho Pharmaceut Co Ltd 貼付剤
JPH10218793A (ja) * 1997-02-03 1998-08-18 Nichiban Co Ltd 経皮吸収型消炎鎮痛用テープ剤及びその製造方法
WO1999018955A1 (fr) * 1997-10-15 1999-04-22 Taisho Pharmaceutical Co., Ltd. Preparation absorbable par voie percutanee
JPH11199484A (ja) * 1998-01-13 1999-07-27 Taisho Pharmaceut Co Ltd 外用剤組成物

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05208909A (ja) * 1991-08-22 1993-08-20 Hoechst Ag 臓器移植における拒絶反応治療用医薬
JPH06329538A (ja) * 1993-03-31 1994-11-29 Hoechst Ag 皮膚疾患処置用薬剤
JPH10158166A (ja) * 1996-12-02 1998-06-16 Taisho Pharmaceut Co Ltd 貼付剤
JPH10218793A (ja) * 1997-02-03 1998-08-18 Nichiban Co Ltd 経皮吸収型消炎鎮痛用テープ剤及びその製造方法
WO1999018955A1 (fr) * 1997-10-15 1999-04-22 Taisho Pharmaceutical Co., Ltd. Preparation absorbable par voie percutanee
JPH11199484A (ja) * 1998-01-13 1999-07-27 Taisho Pharmaceut Co Ltd 外用剤組成物

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008013494A (ja) * 2006-07-06 2008-01-24 Lintec Corp 経皮吸収貼付剤
DE102014201651A1 (de) 2014-01-30 2015-07-30 Georg-August-Universität Göttingen Stiftung Öffentlichen Rechts, Universitätsmedizin Isoxazolderivate zur Verwendung bei der Behandlung und/oder Prophylaxe von Herzerkrankungen
JP2018504436A (ja) * 2015-02-05 2018-02-15 メモリアル スローン−ケタリング キャンサー センター 浮腫の治療のための組成物及び方法
US10874651B2 (en) 2015-02-05 2020-12-29 Memorial Sloan Kettering Cancer Center Compositions and methods for treatment of edema

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